Zoe Berg

Researchers at Yale University are exploring new approaches to treating potentially fatal heart defects. They began designing artificial blood vessels to grow inside patients’ hearts.

After receiving more than $2 million from the National Institutes of Health, School of Medicine bioengineers will begin treating patients with single-ventricular congenital heart disease (SVCHD), a heart disease that affects 1 in 1,000 newborns. We are considering the development of artificial blood vessels. . In many cases, this defect can be fatal without surgery, but infants who are treated probability Of survival.

But the usual procedure, which uses synthetic tubes to reroute blood from a failing heart to the lungs, is not a perfect solution. The graft can become infected, become clogged, or the body can attack the synthetic tube as a foreign object. The tube also does not grow with the patient, so multiple surgeries are required to replace the tube as the child ages.

Researchers at Yale University believe they have a solution: blood vessels made of cells rather than synthetic materials like plastic.

“In our case, we are creating an artificial blood vessel, which can actually grow as the baby gets older,” says Muhammad Riaz, a researcher on the team who studies cardiology. “This will be the ultimate solution.”

fontan surgery

The human heart has four main components. He has two upper chambers, one called the atrium, which receives blood that reaches the heart. The lower chambers, known as ventricles, pump blood out of them.

In patients with single-ventricular congenital heart disease, only one ventricle is strong or large enough to pump blood out of the heart. This includes the lungs. There the blood receives oxygen and is transported to the rest of the body.

According to the defective newborn american heart association, which can make breathing and eating difficult. The lack of oxygen can also cause the skin to turn bluish, a condition called cyanosis.

If left untreated, the defect can be fatal. Doctors get to work as soon as the baby is born, often with a type of open-heart surgery called the Fontan procedure.inside fontanSurgeons use a synthetic graft to send oxygen-poor blood from the lower body directly into the pulmonary artery, bypassing the heart. Once the blood reaches the pulmonary arteries, it travels to the lungs to replenish the oxygen supply of the cells.

However, the synthetic tubes used in Fontan surgery have some drawbacks. In addition to not being able to grow up with your child, you are more susceptible to infections and clotting. In some cases, the body’s immune system may reject the graft and attack it instead.

The Yale team hopes to avoid these complications by using artificial blood vessels made from cellular materials. Biological alternatives grow with the child and can help avoid repeat surgeries. The chances of rejection are also minimized, the scientists said.

“[It is] “It’s a biological tube that can provide mechanical assistance to transport blood effectively,” said Peter Gruber, professor of surgery at the School of Medicine and pediatric cardiac surgeon at Yale-New Haven Children’s Hospital. “[It] Redirects blood flow away from the damaged ventricle of the heart. ”

“Universal vascular graft”

To do so, the team led by Yibin Chiyan, a cardiology expert and associate professor of medicine, is using cells called induced pluripotent stem cells. Unlike cells found in parts of the body such as muscle or liver, stem cells have not yet been specialized to play a specific role in the body. Under the right conditions, they can transform into virtually any type of cell.

Induced pluripotent stem cells (iPSCs) are one example. And through the process of cell reprogramming, scientists can turn most types of specialized or differentiated adult cells back into induced pluripotent stem cells.

Qyang’s group hopes to use iPS cells to generate the cellular building blocks that are essential components of blood vessels: specialized cells known as smooth muscle cells and endothelial cells. Because iPSCs can be reprogrammed from regular cells, the research team hopes to be able to consistently scale production of these cell varieties.

“One of the benefits of using these stem cells is that they can constantly proliferate,” said Hangqi Luo, a postdoctoral fellow in the lab. “So one small cell can generate thousands or tens of thousands of cells that we want.”

However, Riaz pointed out that using iPSCs is not always a smooth process. In some cases, other unwanted cell types may also be generated during the differentiation of stem cells into smooth muscle cells or endothelial cells.

“The first and most important challenge is actually getting enough of the cells that we need to engineer the tissues and blood vessels,” Riaz said. “There were other cell types that contaminated these functional cells. Therefore, these extraneous cell types must be avoided, and it is important to remove unnecessary cells to obtain the pure population of smooth muscle cells that we need. It Is difficult.”

Although no perfect solution has been found yet, Riaz and his colleagues say they are developing or refining ways to reduce the number of unnecessary cells and increase the number of useful cells when building artificial blood vessels. Ta.

And when researchers isolate and culture endothelial and smooth muscle cells from iPSCs, another problem arises. Because the specialized cells used in artificial blood vessels are taken from donors, they have proteins called immune markers attached to their surfaces, Luo said. This protein acts like a unique immune fingerprint that the body can recognize.

These proteins are usually helpful. This is the same mechanism the body’s immune system uses to distinguish its own cells from pathogens, protect blood cells, and attack viruses. However, because the artificial blood vessels come from a donor, they contain immune markers that the body does not recognize.

The result is immune rejection, in which the body’s immune system attacks the artificial graft in the same way it rejects plastic implants.

“That’s the biggest challenge,” Gruber added.

To circumvent the artificial blood vessels’ defense mechanisms, the researchers used a gene-editing technique called CRISPR Cas-9 to delete all immune protein makers on the iPSC cells.

With a clean protein sheet, the final product should be a “universal” cell that is immunocompatible and able to evade the body’s natural defense systems, Luo said.

“Our ultimate goal is to generate a universal vascular graft that is free of immune rejection and can be accepted by any patient,” Luo said.

From mice and rabbits to humans

The researchers said they tested the graft’s ability to withstand high blood pressure in the body and integrate seamlessly with the host’s immune system to minimize the risk of rejection. Luo said part of their current work is to improve the ship’s mechanical strength.

“[The] The mechanical properties are not very strong, but we are working on making them even stronger. [so it] It can tolerate high blood pressure,” Luo said.

This device is still a long way from being used on humans. Professor Luo said trials have so far been successful in which the grafts are implanted in “humanized” rat models that have been genetically engineered to carry specific human genes and tissues, and the immune responses of the rats are examined. That’s what it means.

Luo said they hope to scale up the animal model. The plan is to implant the artificial blood vessels in larger animals, such as rabbits, before moving on to a pig model. If the pig trials are successful, the research team’s next step will be human clinical trials, which Riaz estimates could occur within five to 10 years.

If that happens, vascular grafts could be a promising solution to vascular diseases and injuries beyond congenital heart disease, Riaz added. Bioengineered blood vessels with the ability to grow and evade immune rejection could be used to treat heart disease and repair ends. Gradual heart failure.

“If we can generate this graft using stem cells, and ultimately generate a graft without immune rejection, then we can build any type of graft we want and transplant it into every patient. You can,” Riaz said.

by Centers for Disease Control and PreventionCongenital heart defects affect nearly 1% of births in the United States annually, or approximately 40,000 births.